Method and apparatus for calculating fluid flow rate

ABSTRACT

A switch valve for use in an extracorporeal blood flow circuit comprises a valve housing having a chamber, four openings communicating with the chamber, and a valve member located in the valve chamber. A first opening is to be connected to a patient via an arterial cannula, a second opening is to be connected to a patient via an venous cannula, a third opening is to be connected to a first inlet/outlet of a blood treatment device, and a fourth opening is to be connected to a second inlet/outlet of a blood treatment device. The valve member is movable within the valve housing to fluidly connect the first opening to either the third or the fourth opening and to fluidly connect the second opening to either the third or the fourth opening. The width of the valve member is smaller than a peripheral dimension of the openings.

The present patent application is a divisional application of U.S.patent application Ser. No. 09/425,124 filed on Oct. 22, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method and device for measuring bloodflow rate in a blood access. Blood is taken out from the body of amammal to an extracorporeal blood circuit through a blood access, vianeedles or a catheter.

2. Description of the Related Art

There are several types of treatments in which blood is taken out in anextracorporeal blood circuit. Such treatments involve, for example,hemodialysis, hemofiltration, hemodiafiltration, plasmapheresis, bloodcomponent separation, blood oxygenation, etc. Normally, blood is removedfrom a blood vessel at an access site and returned to the same bloodvessel or at another location in the body.

In hemodialysis and similar treatments, an access site is commonlysurgically created in the nature of a fistula. Blood needles areinserted in the area of the fistula. Blood is taken out from the fistulavia an arterial needle and blood is returned to the fistula via a venousneedle.

A common method of generating a permanent access site having capabilityof providing a high blood flow and being operative during several yearsand even tens of years, is the provision of an arterio-venous fistula.It is produced by operatively connecting the radial artery to thecephalic vein at the level of the forearm. The venous limb of thefistula thickens during the course of several months, permittingrepeated insertion of dialysis needles.

An alternative to the arterio-venous fistula is the arterio-venousgraft, in which a connection is generated from, for example, the radialartery at the wrist to the basilic vein. The connection is made with atube graft made from autogenous saphenous vein or frompolytetrafluorethylene (PTFE, Teflon). The needles are inserted in thegraft.

A third method for blood access is to use a silicon, dual-lumen cathetersurgically implanted into one of the large veins.

Further methods find use in specific situations, like a no-needlearterio-venous graft consisting of a T-tube linked to a standard PTFEgraft. The T-tube is implanted in the skin.

Vascular access is obtained either by unscrewing a plastic plug or bypuncturing a septum of said T-tube with a needle. Other methods are alsoknown.

During hemodialysis, it is desirable to obtain a constant blood flowrate of 150-500 ml/min or even higher, and the access site must beprepared for delivering such flow rates. The blood flow in an AV fistulais often 800 ml/min or larger, permitting delivery of a blood flow ratein the desired range.

In the absence of a sufficient forward blood flow, the extracorporealcircuit blood pump will take up some of the already treated bloodentering the fistula via the venous needle, so called access or fistularecirculation, leading to poor treatment results.

The most common cause of poor flow with AV fistulas is partialobstruction of the venous limb due to fibrosis secondary to multiplevenipunctures. Moreover, stenosis causes a reduction of access flow.

When there is a problem with access flow, it has been found that accessflow rate often exhibit a long plateau time period with reduced butsufficient access flow, followed by a short period of a few weeks withmarkedly reduced access flow leading to recirculation and ultimatelyaccess failure. By constantly monitoring the evolution of the accessflow during consecutive treatment sessions, it is possible to detectimminent access flow problems.

Several methods have been suggested for monitoring recirculation andaccess flow. Many of these methods involve injection of a markersubstance in blood, and the resultant recirculation is detected. Themethods normally involve measurement of a property in the extracorporealblood circuit. Examples of such methods can be found in U.S. Pat. No.5,685,989, U.S. Pat. No. 5,595,182, U.S. Pat. No. 5,453,576, U.S. Pat.No. 5,510,716, U.S. Pat. No. 5,510,717, U.S. Pat. No. 5,312,550, etc.

Such methods have the disadvantage that they cannot detect when theaccess flow has decreased to such an extent that recirculation is atrisk, but only when recirculation prevails. Moreover, it is a drawbackthat injection of a substance is necessary.

A noninvasive technique that allows imaging of flow through AV grafts iscolor Doppler ultrasound. However, this technique requires expensiveequipment.

The measurement of access flow rate necessitates the reversal of theflows in the extracorporeal circuit. A valve for such reversal is shownin i.a. U.S. Pat. No. 5,605,630 and U.S. Pat. No. 5,894,011. However,these valve constructions comprise dead ends in which blood may standstill for a long time and coagulate, which is a drawback.

BRIEF SUMMARY OF INVENTION

An object of the present invention is to provide a method and a devicefor measuring the access flow rate without interfering with the bloodand without injecting a substance in blood.

Another object of the invention is to provide a method and a device formeasuring access flow rate without measuring on the blood in theextracorporeal blood circuit or in the access or blood vessel.

According to the invention, it is required to reverse the blood flowthrough the access. Thus, a further object of the invention is toprovide a valve for reversing the blood flow.

A still further object of the invention is to provide a method fordetermining when the blood flow rate is so small that risk forrecirculation prevails.

These objects are achieved with a method and an apparatus for estimatingfluid flow rate (Qa) in a fluid flow access, comprising removing a firstfluid flow from said access at a removal position to an external flowcircuit comprising a dialyzer having a semipermeable membrane, saidfirst fluid flow passing along said membrane at one side thereof and adialysis fluid being emitted from the other side thereof, and returningsaid first fluid flow from said external flow circuit to said access ata return position downstream of said removal position, measuring a firstvariable which is essentially proportional to a concentration (Cd norm)of a substance in said dialysis fluid emitted from the dialyzer,reversing the removal position with the return position and measuring asecond variable which is essentially proportional to the concentration(Cd rev) of said substance in said dialysis fluid in the reversedposition; and calculating the fluid flow rate (Qa) in said flow accessfrom said measured concentrations.

Preferably, the calculation of the fluid flow rate in said flow accesstakes place by calculating the ratio between the first and the secondvariable and using the formula: Cd norm/Cd rev=1+K/Qa, in which Cd normand Cd rev are values proportional to the concentrations of saidsubstance in the dialysis fluid in the normal and reversed positions,respectively, and K is the clearance of the dialyzer and Qa is theaccess flow rate.

The blood flow access may be in a mammal for obtaining access to a bloodvessel, such as a hemodialysis access in the nature of an arterio-venousshunt or fistula. In the latter case, the dialyzer clearance K isreplaced by the effective dialyzer clearance Keff obtained by takinginto account a cardiopulmonary recirculation and in the normal position.

The substance is preferably selected from the group of: urea,creatinine, vitamin B12, beta-two-microglobuline and glucose, or may bean ion selected from the group of: Na⁺, Cl⁻, K⁺, Mg⁺⁺, Ca⁺⁺, HCO₃ ⁻,acetate ion, or any combination thereof as measured by conductivity; andwherein said concentration is measured as the concentration differencebetween the outlet and the inlet of the dialyzer, if applicable.

It is possible to measure the actual concentration of the substance.However, since only the ratio between the concentrations in the normaland the reversed position, respectively, is needed, it is possible tomeasure a value, which is proportional to the concentration of saidsubstance, whereby said value is used in place of said concentration.Said property may be the blood concentration of said substance in theexternal circuit, either before or after the dialyzer. Alternatively,the relative whole body efficiency (Kwh/V) may be used, as explained inmore detail below.

The effective clearance Keff may be obtained by the equation Keff=Qd*Cd/Cs, where Qd is the flow of dialysis fluid emitted from thedialyzer, Cd is the concentration of said substance in said dialysisfluid and Cs is the concentration of said substance in systemic venousblood.

A method of measuring the concentration (Cs) of said substance insystemic venous blood comprises the steps of: stopping the blood flow inthe external flow circuit for a time period sufficient to allow thecardiopulmonary circulation to equalize; starting the blood flow in theexternal flow circuit with a slow speed to fill the arterial line withfresh blood before the measurement; and measuring the equalizedconcentration of said substance in the dialysis fluid at a low dialysateflow rate or at isolated ultrafiltration. It is advantageous to make themeasurement of the effective clearance at the initiation of thetreatment.

The concentration (Cs) of said substance in systemic venous blood may beestimated by: calculating a whole body mass of urea (Murea) in the bodyof the patient, estimating or measuring the distribution volume (V) ofurea in the body of the patient; and estimating the concentration (Cs)of said substance in the blood by dividing the whole body mass of ureawith the distribution volume. In this way, the mean concentration ofurea in the whole body is obtained. However, the mean concentration inthe whole body is slightly higher than the urea concentration in thesystemic blood, except at the start of the treatment. Thus, thiscalculation should preferably be done or be extrapolated to the start ofthe treatment.

It is possible to discriminate between the condition when access orfistula recirculation has developed and not. A method for that purposewould be: changing the blood flow rate (Qb); monitoring theconcentration of said substance in the dialysate emitted from thedialyzer; and detecting a possible fistula recirculation in the normalposition by correlating a change in said concentration to said change ofthe blood flow rate.

Preferably, the blood flow rate is decreased and a correspondingdecrease in the urea concentration is monitored, and the absence of sucha decrease being indicative of fistula recirculation.

BRIEF DESCRIPTION OF DRAWINGS

Further objects, advantages and features of the invention appears fromthe following detailed description of the invention with reference tospecific embodiments of the invention shown on the drawings, in which

FIG. 1 is a partially schematic view of a forearm of a patient providedwith an AV fistula;

FIG. 2 is a schematic diagram of an extracorporeal dialysis circuit;

FIG. 3 is a schematic diagram of the blood flow circuit in a patient andin the attached extracorporeal blood circuit;

FIG. 4 is a schematic diagram similar to FIG. 3, but with theextracorporeal circuit in an alternative reversed position;

FIG. 5 is a schematic diagram of a blood flow circuit including a switchvalve;

FIG. 6 is a diagram of the dialysis fluid urea concentration versustime, including a portion with reversed flow access according to theinvention;

FIG. 7 is a schematic diagram similar to the diagram of FIG. 5comprising an alternative valve arrangement;

FIG. 8 is schematic diagram similar to the diagram of FIG. 7 showing thevalve arrangement in an idle position;

FIG. 9 is schematic diagram similar to the diagram of FIG. 7 showing thevalve arrangement in a reversed position;

FIG. 10 is a schematic diagram similar to FIG. 5 with the pump in analternative position;

FIG. 11 is a diagram showing calculations with relative whole bodyefficiency;

FIG. 12 is a cross-sectional view of a valve housing to be used in theschematic diagram of FIGS. 5 and 7 to 10;

FIG. 13 is a bottom view of a valve member intended to be inserted inthe valve housing of FIG. 12; and

FIG. 14 is a partially schematic plan view of the valve housing of FIG.12.

DETAILED DESCRIPTION OF INVENTION

For the purpose of this description, an access site is a site in which afluid in a tube can be accessed and removed from and/or returned to thetube. The tube may be a blood vessel of a mammal, or any other tube inwhich a fluid is flowing. The access flow rate is the flow rate of thefluid in the tube or blood vessel immediately upstream of the accesssite or removal position.

FIG. 1 discloses a forearm 1 of a human patient. The forearm 1 comprisesan artery 2, in this case the radial artery, and a vein 3, in this casethe cephalic vein. Openings are surgically created in the artery 2 andthe vein 3 and the openings are connected to form a fistula 4, in whichthe arterial blood flow is cross-circuited to the vein. Due to thefistula, the blood flow through the artery and vein is increased and thevein forms a thickened area downstream of the connecting openings. Whenthe fistula has matured after a few months, the vein is thicker and maybe punctured repeatedly. Normally, the thickened vein area is called afistula.

An arterial needle 5 is placed in the fistula, in the enlarged veinclose to the connected openings and a venous needle 6 is placeddownstream of the arterial needle, normally at least five centimetersdownstream thereof.

The needles 5 and 6 are connected to a tube system 7, shown in FIG. 2,forming an extracorporeal circuit comprising a blood pump 8, such as adialysis circuit. The blood pump propels blood from the blood vessel,through the arterial needle, the extracorporeal circuit, the venousneedle and back into the blood vessel.

The extracorporeal blood circuit 7 shown in FIG. 2 further comprises anarterial clamp 9 and a venous clamp 10 for isolating the patient fromthe extracorporeal circuit should an error occur.

Downstream of pump 8 is a dialyzer 11, comprising a blood compartment 12and a dialysis fluid compartment 13 separated by a semipermeablemembrane 14. Further downstream of the dialyzer is a drip chamber 15,separating air from the blood therein.

Blood passes from the arterial needle past the arterial clamp 9 to theblood pump 8. The blood pump drives the blood through the dialyzer 11and further via the drip chamber 15 and past the venous clamp 10 back tothe patient via the venous needle. The drip chamber may comprise an airdetector, adapted to trigger an alarm should the blood emitted from thedrip chamber comprise air or air bubbles. The blood circuit may comprisefurther components, such as pressure sensors etc.

The dialysis fluid compartment 13 of the dialyzer 11 is provided withdialysis fluid via a first pump 16, which obtains dialysis fluid from asource of pure water, normally RO-water, and one or several concentratesof ions, metering pumps 17 and 18 being shown for metering suchconcentrates. The preparation of dialysis fluid is conventional and isnot further described here.

An exchange of substances between the blood and the dialysis fluid takesplace in the dialyzer through the semipermeable membrane. Notably, ureais passed from the blood, through the semipermeable membrane and to thedialysis fluid present at the other side of the membrane. The exchangemay take place by diffusion under the influence of a concentrationgradient, so called hemodialysis, and/or by convection due to a flow ofliquid from the blood to the dialysis fluid, so called ultrafiltration,which is an important feature of hemodiafiltration or hemofiltration.

From the dialysis fluid compartment 13 of the dialyzer is emitted afluid called the dialysate, which is driven by a second pump 19 via aurea monitor 20 to drain. The urea monitor continuously measures theurea concentration in the dialysate emitted from the dialyzer, toprovide a dialysate urea concentration curve during a dialysistreatment. Such urea concentration curve may be used for severalpurposes, such as obtaining a total body urea mass, as described in WO9855166, and to obtain a prediction of the whole body dialysis dose Kt/Vas also described in said application. The content of WO 9855166 isincorporated in the present specification by reference.

As described above, the present invention provides a method ofnon-invasively measuring the access flow in the fistula immediatelybefore the arterial needle, using the urea monitor and the dialysiscircuit as shown in FIG. 2.

By measuring the dialysis urea concentration during normal dialysis andthen reversing the positions of the needles and measuring the dialysisurea concentration with the needles in the reversed position, it ispossible to calculate the blood flow in the blood access, without theaddition of any substance to blood or the dialysis fluid.

FIG. 3 shows a simplified schematic diagram of the blood vessel circuitof a patient and a portion of the dialysis circuit according to FIG. 2.The patient blood circuit comprises the heart, where the right chamberof the heart is symbolized by an upper pump 21 and the left chamber ofthe heart is symbolized by a lower pump 22. The lungs 23 are locatedbetween the upper and lower pump. From the outlet of the left chamberpump 22 of the heart, the blood flow divides into a first branch 24leading to the access 25, normally in the left forearm of the patient,and a second branch 26 leading to the rest of the body, such as organs,other limbs, head, etc. symbolized by a block 27. Blood returning fromthe body from the organs etc., i.e. from block 27, combines with bloodreturning from the access and enters the right chamber pump 21.

The cardiac output flow rate is defined as Qco and the flow rate of theaccess is defined as Qa, which means that Qco−Qa enters the block 27.The venous blood returning from block 27 before being mixed with bloodfrom the access, the systemic venous blood, has a urea concentration ofCs. The blood leaving the left chamber pump 22 has a urea concentrationof Ca equal to that passing out to the access 25 as well as to the block27.

For measuring the access flow rate, it is necessary to reverse the flowthrough the arterial and venous needles. One way of achieving that is toreverse the needles manually.

Alternatively, FIG. 5 shows a valve 28 for performing the sameoperation. The arterial needle 5 is connected to an arterial inlet line29 of the valve and the venous needle 6 is connected to a venous inletline 30 of the valve. The blood pump is connected to a first outlet line31 of the valve and the returning blood from the dialyzer 11 isconnected to a second outlet line 32 of the valve.

The valve comprises a valve housing and a pivotable valve member 33,which is pivotable from the normal position shown on the drawing to areverse position pivoted 900 in relation to the normal position.

In the normal position shown in FIG. 5, the arterial needle 5 isconnected to the blood pump 8 and the venous needle 6 is connected tothe outlet of the dialyzer, via the drip chamber, see FIG. 2. In thereversed position, the arterial needle 5 is connected to the outlet ofthe dialyzer and the venous needle 6 is connected to the blood pump 8,as required.

An alternative design of the valve arrangement is shown in FIGS. 7, 8and 9. In the embodiment of FIG. 7, the arterial line 29 is connected toan enlarged opening 29 a and the venous outlet line 30 is connected toan enlarged opening 30 a, the openings being arranged in the valvehousing 28 a diametrically opposite to each other. Two enlarged openings31 a and 32 a are arranged in the valve housing 28 a diametricallyopposite each other and displaced 90° in relation to enlarged openings29 a and 30 a. The pivotable valve member 33 a is normally arranged asshown in FIG. 7 and forms a partition dividing the valve chamber in twosemi-circular portions. The valve member has a width, which is smallerthan the peripheral dimension of the enlarged openings. The valve memberis pivotable 900 to a reverse position, shown in FIG. 9, in which theblood flows through the arterial and venous needles are reversed.

During its movement from the normal to the reversed position, the valvemember 33 a passes through an idle position shown in FIG. 8, in whichall four enlarged openings are interconnected, because the width of thevalve member is smaller than the peripheral dimension of the enlargedopenings. By this idle position, harm to blood cells may be avoided.Such harm may be caused by high shear stresses, which may occur if theinlet line 31 to the blood pump or the outlet line 32 from the dialyzeris completely occluded. By means of the idle position, another advantageis obtained, that the blood needles are not exposed to rapid change offlows, which in some instances even may result in dislocation of theneedles. When the valve member is moved from the normal position to theidle position, the flow through the needles change from the normal flowof, for example, 250 ml/min to essentially zero flow. The valve membermay be placed in the idle position for some seconds. Then, the valvemember is moved to the reversed position, and the flows through theneedles are changed from essentially zero flow to −250 ml/min. In thisway, a gentler switch between normal and reversed flows may be obtained.

It is noted, that the positions of the openings and the valve member maybe different so that the pivotal movement may be less than or more than90°. Moreover, the openings need not be arranged diametrically in orderto achieve the desired operation. Furthermore, the dimensions of theenlarged openings in relation to the tubes and lines are not in scale,but the diameter of the enlarged openings is rather of the samedimension as the tube inner diameter, as appears more clearly below.

It is noted that the valve is constructed to have as few dead endportions as possible, in which the blood may stand still and coagulate.From the drawing, it is appreciated that no portion of the valve has adead end construction in any position of the valve body.

Furthermore, another schematic diagram incorporating a valve is shown inFIG. 10. FIG. 10 differs from FIG. 5 only in the placement of the pump 8a, which in the embodiment according to FIG. 10 is placed between thearterial needle 5 and the valve 28. In this manner, the pressure acrossthe valve body 33 is less compared to the embodiment according to FIG.5. The operation is somewhat different. The blood pump is stopped, andthe valve is put in the reversed position. Finally, the pump is startedand pumping the blood in the opposite direction by reversing therotational direction of the pump.

In order to ascertain that no air is introduced into the patient ineither position of the valve, it may be advantageous to add an airdetector 34 and 35 immediately before each of the arterial and venousneedle, or at least before the arterial needle. The air detectorstrigger an alarm should they measure air bubbles in the blood given backto the blood vessel. Normally, the air detector in the drip chamber issufficient for this purpose.

The detailed construction of a valve intended to be used in the presentinvention, is disclosed in FIGS. 12, 13 and 14. The valve comprises avalve housing 36 comprising two inlet connectors and two outletconnectors. All four connectors open into cylindrical valve chamber 41,the four openings being displaced 90° in relation to each other.

As shown in FIG. 14, the valve comprises a blood inlet connector 37connected to the arterial needle 5 and a blood outlet connector 38connected to the venous needle 6. The connector portions are arranged asmale Luer connectors to be connected to flexible tubes ending with afemale Luer connector.

Furthermore, the valve comprises a circuit outlet connector 39 connectedto the blood pump 8 and a circuit inlet connector 40 connected to thedialyzer outlet. The connector portions 39 and 40 are arranged as femaleLuer connectors to mate with male Luer connectors of the circuit.

As appears from FIG. 12, the cylindrical valve chamber 41 is closed atthe bottom. From the top, a valve member 42 may be introduced into thecylindrical valve chamber. The valve member 42 comprises a valvepartition 43 as appears from FIG. 13.

The valve member also comprises an operating wing 44, by means of whichthe valve member may be pivoted 900 between a normal position, in whichthe valve partition 43 is situated as shown by dotted lines in FIG. 14,and a reversed position. The pivotal movement is limited by a shoulder45 of the valve member 42, which cooperates with a groove 46 in thevalve housing. The shoulder 45 is provided with a protrusion 46 a thatcooperates with two recesses 47 and 48 in the normal position andreverse position, respectively, to maintain the valve member in eitherposition. The groove 46 may be provided with a third recess (not shownin the drawing) in order to define said idle position. Such a thirdrecess is positioned in the middle between the two recesses 47 and 48.

The valve member and housing are provided with suitable sealing toensure safe operation. The operation of the valve is evident from theabove description.

By studying the theoretical dialysate urea concentrations resulting froma given dialyzer clearance K, a given access blood flow Qa and a givenblood urea concentration Cs in the systemic venous blood returning fromthe body, it is found that the effective urea clearance Keff of thedialyzer, taking the cardiopulmonary recirculation into account, isneeded for the calculation of access flow. The effective clearance canbe measured, for example as described in EP 658 352, the contents ofwhich is incorporated in the present application by reference.

Alternatively, the effective clearance can be calculated fromsimultaneous systemic venous blood Cs and dialysate Cd measurements ofurea concentrations, such as by blood samples.

The systemic blood urea concentration Cs may be measured by the socalled stop flow—slow flow technique, where the blood flow issubstantially stopped for a couple of minutes to allow thecardiopulmonary recirculation to equalize. Thereafter, the pump is runslowly to fill the arterial line with fresh blood before taking theblood sample. The urea concentration in the so obtained blood sample isequal to the urea concentration Cs in the systemic venous bloodreturning from the body to the heart.

Alternatively to taking a blood sample, the dialysis fluid flow at theother side of the membrane is stopped and the slowly flowing blood isallowed to equalize with the dialysate at the other side of themembrane, whereupon the urea concentration of the dialysate is measuredto obtain the systemic venous blood urea concentration Cs.

A further method to obtain effective clearance is described in WO9929355. According to the invention described in WO 9929355, thesystemic blood concentration Cs is measured before or at the initiationof the treatment, for example by stop flow—slow flow technique withblood sample or equalization as described above. After obtaining validdialysate urea concentration values Cd from a urea monitor connected tothe dialyzer outlet line, the initial dialysate urea concentrationCdinit at the start of the treatment is extrapolated by the dialysateurea curve obtained. The content of WO 9929355 is incorporated herein byreference.

A still further method of obtaining systemic blood urea concentration Csis to calculate the urea mass Mwh in the whole body and extrapolate theurea mass to the start of the treatment. By dividing the whole body ureamass Mwh with the distribution volume V, the systemic blood ureaconcentration Cs at the start of the treatment is obtained.

By dividing the dialysate urea concentration Cd with the systemic bloodurea concentration Cs and multiplying with the dialysate flow rate Qd,the effective clearance Keff is obtained. It is advantageous to measurethe effective clearance Keff at the initiation of the treatment.

Furthermore, in the method of the invention, the blood flows in thearterial and venous needles are reversed. The dialysate ureaconcentrations in the two cases with normal position of the needles andwith reverse position of the needles may be calculated as follows, withreference to FIGS. 3 and 4.

The blood urea concentration Cs in the venous blood returning from thebody is assumed unchanged when the lines are reversed, and the dialyzerclearance K is also assumed unchanged. For simplicity ultrafiltration isassumed to be zero, but it is also possible to handle a nonzero UF.

The following notations are used:

-   Qco—Cardiac Output-   Qa—Access flow-   Qb—Blood flow in extracorporeal circuit-   Qd—Dialysate flow-   K—Dialyzer clearance-   Keff—Effective dialyzer clearance-   Cs—Blood urea concentration in systemic venous blood returning from    the body-   Ca—Blood urea concentration in the access-   Cb—Blood urea concentration at the dialyzer inlet-   Cd—Dialysate urea concentration    The definition of clearance is:

K=(removed urea)/Cb=Qd *Cd/Cb  (1)

Consider first the case in which Qa>Qb and the needles are in the normalposition. In this case Cb=Ca.

Removal from blood must equal appearance in the dialysate so that

K*Ca=Qd*Cd  (2)

A mass balance for urea at the point V, see FIG. 3, when mixing thevenous return blood with the blood from the access gives:

Ca*Qco=Cs*(Qco−Qa)+Ca*(Qa−K)  (3)

Thus, we obtain a relation between Ca and Cs.By combining equations 2 and 3 we obtain:

Cd=(K/Qd)*Cs/[1+K/(Qco−Qa)]  (4)

The definition of effective clearance Keff implies that Cs should beused in the denominator instead of Cb as normally used in dialyzerclearance, which means that

Keff=K*(Cb/Cs)=K/[1+K/(Qco−Qa)]  (5)

If we now turn to the case with reversed lines, see FIG. 4, we stillhave that what is removed from the blood must enter the dialysate, sothat in this case

K*Cb=Qd*Cd  (6)

The flow in the fistula between the needles will be Qa+Qb and we cancalculate the blood urea concentration at the dialyzer inlet from a ureamass balance at the point P where the dialyzed blood enters the accessagain

Cb*(Qb−K)+Ca *Qa=Cb*(Qb+Qa)  (7)

We also have the mass balance at the point Q where the venous returnblood meets the dialyzed blood in the access return flow:

Ca *Qco=Cs*(Qco−Qa)+Cb *Qa  (8)

By eliminating Ca and Cb we get

Cd=(K/Qd)*Cs/[1+(Qco/Qa)*K/(Qco−Qa)]  (9)

Since Cs, K and Qd in the two cases are unchanged, it is possible toobtain the ratio of dialysate urea concentrations:

$\begin{matrix}\begin{matrix}{{{Cd}\mspace{14mu} {{norm}/{Cd}}\mspace{14mu} {rev}} = {{1 + {( {K/{Qa}} )/\lbrack {1 + {K/( {{Qco} - {Qa}} )}} \rbrack}} =}} \\{= {1 + {{Keff}/{Qa}}}}\end{matrix} & (10)\end{matrix}$

In practice, the two dialysate urea concentrations are probably bestfound by a curve fit to the dialysate urea curves before and after theswitch of lines, with an extrapolation to the time of switching from therespective side, see FIG. 6, which shows the urea concentration Cd ofthe dialysate during a normal hemodialysis treatment.

During a time period of about 10 minutes, marked with a ring in FIG. 6,the arterial and venous needles are reversed. After an initial timeperiod for allowing the urea monitor to measure accurately, the ureaconcentration with reversed lines is approximately 0.8 times theoriginal urea concentration, which means that Cdnorm/Cdrev=1.25. Thus,if Keff is 200 ml/min, as measured with the needles in the normalposition or estimated as described above, the access flow is 800 ml/min.

The effective clearance may also be obtained as a rough estimate fromblood and dialyzer flows and dialyzer characteristics, e.g. from thedialyzer date sheet.

In the present specification, there are used three different clearances,namely dialyzer clearance, effective clearance and whole body clearance.If dialyzer clearance is 250 ml/min for a certain blood flow rate anddialysate flow rate, the effective clearance is normally 5 to 10% lower,such as 230 ml/min. The whole body clearance is still 5 to 15% lower,such as 200 ml/min. The dialyzer clearance is the clearance as measureddirectly on the dialyzer. The effective clearance is the clearance alsotaking into account the cardio-pulmonary recirculation. Finally, thewhole body clearance is the effective clearance further taking intoaccount other membranes in the body restricting the flow of urea fromany part of the body to the dialysate. The concept of whole bodyclearance is described in WO 9855166, the content of which is herewithincorporated by reference.

The effective clearance used in the formula may also be obtained from ameasurement according to the method described in EP 658 352 mentionedabove, with the needles in the normal position. This will give a measureof the effective plasma water urea clearance, which then has to beconverted to whole blood clearance. The method of EP 658 352 essentiallycomprises that the conductivity of the dialysis fluid upstream of thedialyzer is increased by for example 10% and then returned to theoriginal value. The result at the outlet side of the dialyzer ismeasured and results in a measure of the effective clearance Keff of thedialyzer.

Alternatively, the effective clearance may be calculated according toequation Kef f=Qd *Cd/Cs. The systemic venous urea concentration may bemeasured at the same time as the dialysate urea concentration Cd, or bythe methods described above.

Another method would be to use the value of total body urea mass Mureaobtained by the method according to WO 9855166, mentioned above. Byobtaining the urea distribution volume V by Watsons formula or any othermethod, the venous urea concentration would be approximately:

Cs=Murea/V  (11)

In the method of WO 9855166, the relative whole body efficiency of thedialyzing process Kwb/V is obtained. Note, that whole body clearance isused, as indicated by the subscript wb. According to said WO 9855166,urea concentration is proportional to the relative whole body efficiencyaccording to the formula:

Kwb/V=(Qd *Cd)/m  (12)

Thus, if (Kwb/V) is used instead of Cd in the above equation (10), asimilar result is obtained, if it is presumed that m is constant, i.e.the measurement must be extrapolated to the same time instance:

(Kwb/V)norm/(Kwb/V)rev=1+Keff/Qa  (13)

As is mentioned in said WO 9855166, it is possible to calculate therelative whole body efficiency only from dialysate urea measurement.Since we are interested only in the ratio in the normal and reversedposition, we do not need to calculate the actual Kwh.

FIG. 11 shows a plot of the relative whole body efficiency K/V (min⁻¹).The period with reversed lines is shown inside a circle. In all otherrespects, the same discussion applies as is given above.

The calculations above assume that the extracorporeal blood flow rate Qbdoes not exceed the access flow rate Qa. If this is the case there willbe access recirculation and the flow in the access will be reversed whenthe needles are in the normal position. The calculation of dialysateurea concentration is unchanged for the needles in reversed position,but has to be modified for the needles in normal position. Calculationscorresponding to those above show that the ratio above between dialysateurea concentrations for normal and reversed needle positions will be:

Cd norm/Cd rev=1+Keff/Qb  (14)

where Keff is the effective clearance with the effect of recirculationincluded, that is with the needles in the normal position.

The only difference is that the calculation will now give theextracorporeal blood flow Qb instead of the access flow. This blood flowis known, so in practice this means that when the result is an accessflow rate Qa close to the blood flow rate Qb, recirculation should besuspected, and this always means that the access has to be improved.

Keff/Qb is a figure lower than one, normally for example 0.6-0.9.Keff/Qa should be considerably lower, for example 0.1-0.4. Thus, when Cdnorm/Cd rev approaches or is lower than a predetermined number, such as1.2 or 1.5, further calculations should be done for determining ifaccess recirculation is present.

A simple procedure is to decrease the blood flow Qb somewhat. If thedialysate concentration then decreases, this means that there is noaccess or fistula recirculation at least at the lower blood flow.

The above calculations can also be made for the situation whereultrafiltration is present. However, it is a simple measure to reducethe ultrafiltration to zero during the measurement interval. Moreover,the error induced by ultrafiltration is small and may be neglected.

The measurement should be performed during a time interval, which isconsiderably larger than 30 seconds so that cardio-pulmonaryrecirculation has been developed. The measurement time for obtainingvalid results may be 5 minutes with the needles reversed, whilemeasurements with the needles in correct position may be done in 5minutes or continuously during the treatment.

The method is also applicable to the methods of treatment comprisinginfusion of a dialysis solution to the blood before or after thedialyzer, called hemofiltration and hemodiafiltration. The result is thesame as given above.

If the access is a venous catheter, there is no cardio-pulmonaryrecirculation and the calculation becomes simpler. The result is thesame, except that the effective clearance Keff is replaced by thedialyzer clearance K, since the systemic venous urea concentration Csbecomes the same as the dialyzer inlet urea concentration Cb.

It should be noted that all flow rates, clearances and ureaconcentrations in the calculations relate to whole blood.

Approximately 93% of plasma is water, depending on the proteinconcentration, and about 72% of erythrocytes is water. Depending on thehematocrit value, the blood water volume is 10-13% lower than the volumeof whole blood, see for example Handbook of Dialysis, Second Edition,John T. Daugirdas and Todd. S Ing, 1994, page 18.

The effective urea clearance obtained according to EP 658 352 relates toblood water, and must therefore be increased by 10-13% before being usedin the present formulas. Blood urea concentration values obtained from alaboratory relate in general to plasma, and must therefore be decreasedby about 7% in order to relate to whole blood.

Alternatively, all urea concentrations, flow rates and clearances may beused as relating to blood water. The effective clearance is then usedunchanged, but the calculated access flow will relate to blood water,and has to be increased by 10-13% to relate to whole blood.

The invention has been described above with reference to use in thehuman body and using urea as a marker for measuring access flow.However, any other substance present in blood and which can be measuredat the dialysate side of the dialyzer may be used according to theinvention, such as creatinine, vitamin B12, beta-two-microglobuline,NaCl or any combination of ions. Another alternative is to measureconductivity.

It is also possible to measure a property proportional to theconcentration, since it is the ratio that is involved in the equations.Thus, urea concentration may be measured by measuring conductivitydifferences after passing the urea containing fluid through a ureasecolumn, and such conductivity difference can be used directly in placeof the concentration values in the equations.

Other indirect methods of measuring any of the above-mentionedsubstances concentrations may be used as long as the measurements aremade at the dialysate side of the dialyzer. Another alternative is tomeasure the blood urea concentrations by any known method, either beforeor after the dialyzer, since these concentrations are proportional tothe concentrations in the formulas.

The invention has been described above with reference to use in thehuman body. However, the invention can be used in any tube system wherea fluid is passed and a portion thereof is taken out for dialysis, suchas in beer or wine production.

1-28. (canceled)
 29. A method of estimating fluid flow rate (Qa) in afluid flow access, comprising: in a normal position, removing a firstfluid flow from said access at a removal position to an external flowcircuit comprising a dialyzer having a semipermeable membrane, saidfirst fluid flow passing along said membrane at one side thereof and adialysis fluid being emitted from the other side thereof, and returningsaid first fluid flow from said external flow circuit to said access ata return position downstream of said removal position; measuring a firstconductivity of the dialysis fluid emitted from the dialyzer in saidnormal position; in a reversed position wherein the removal position andthe return position are reversed, removing a second fluid flow andmeasuring a second conductivity of the dialysis fluid emitted from thedialyzer in said reversed position; and calculating the fluid flow rate(Qa) in said flow access utilizing said measured first and secondconductivities.
 30. The method of claim 29, wherein calculating thefluid flow rate (Qa) in said flow access takes place by the formula: Cdnorm/Cd rev=1+K/Qa in which Cd norm and Cd rev are values proportionalto the conductivity of the dialysis fluid in the normal and reversedpositions, respectively, and K is the clearance of the dialyzer and Qais the access flow rate, wherein conductivity of the dialysis fluid ismeasured as the conductivity difference between dialysis fluid at thedialyzer outlet and dialysis fluid at the dialyzer inlet.
 31. The methodas claimed in claim 30, wherein said flow access is a blood flow accessin a mammal.
 32. The method as claimed in claim 31, wherein said flowaccess is a hemodialysis access in the nature of an arterio-venous shuntor fistula, and wherein the dialyzer clearance K is replaced by theeffective dialyzer clearance Keff obtained by taking into account acardiopulmonary recirculation.
 33. The method of claim 32, wherein saidKeff is obtained by the equationKeff=Qd*Cd/Cs where Qd is the flow of dialysis fluid emitted from thedialyzer, Cd is the conductivity of the dialysis fluid and Cs is theconductivity of systemic venous blood, wherein conductivity of thesystemic venous blood is measured as the conductivity difference betweensystemic venous blood at the dialyzer inlet and dialysis fluid at thedialyzer inlet.
 34. The method of claim 33, wherein the conductivity ofthe systemic venous blood is measured by: stopping the blood flow in theexternal flow circuit for a time period sufficient to allow thecardiopulmonary circulation to equalize; starting the blood flow in theexternal flow circuit with a slow speed to fill the arterial line withfresh blood before the measurement; measuring the equalized conductivityof the dialysis fluid at a low dialysate flow rate or at isolatedultrafiltration.
 35. An apparatus for extracorporeal blood treatmentcomprising: a dialyzer having first and second compartments separated bya semi-permeable membrane; a blood circuit having; a blood removal linefor connecting, in a normal condition, an inlet of the first compartmentto a blood access of a patient at a first connecting point, and a bloodreturn line for connecting, in the normal condition, an outlet of thefirst compartment to the blood access of the patient at a secondconnecting point; a reversal means for switching the connection of theblood removal line and the blood return line to the blood access sothat, in a reverse condition, the first connecting point is in fluidcommunication with the outlet of the first compartment and the secondconnecting point is in fluid communication with the inlet of the firstcompartment; a dialysis liquid circuit having: a dialysis liquid linefor supplying a dialysis liquid to an inlet of the second compartment,and a dialysate line for draining a dialysate from an outlet of thesecond compartment; a sensor connected to the dialysate line formeasuring, in the normal condition, a first conductivity of thedialysate, and for measuring, in the reverse condition, a secondconductivity of the dialysate; a calculating means for calculating afluid flow rate (Qa) in the blood access from the first and secondconductivities and from a clearance of the dialyzer.
 36. The apparatusof claim 35, wherein the calculating means calculates the fluid flowrate (Qa) in the blood access by the formula: Cd norm/Cd rev=1+K/Qa inwhich Cd norm and Cd rev are values proportional to the conductivitiesof said dialysate in the normal and reversed conditions, respectively,and K is the clearance of the dialyzer and Qa is the access flow rate,wherein conductivity of the dialysate is measured as the conductivitydifference between dialysate at the dialyzer outlet and dialysis liquidat the dialyzer inlet.
 37. The apparatus as claimed in claim 36, whereinthe blood access is a hemodialysis access in the nature of anarterio-venous shunt or fistula, and wherein the dialyzer clearance K isreplaced by the effective dialyzer clearance Keff obtained by takinginto account a cardiopulmonary recirculation.
 38. The apparatus of claim37, wherein said clearance Keff is obtained by the equationKeff=Qd*Cd/Cs where Qd is the flow of dialysate, Cd is the conductivityof said dialysate and Cs is the conductivity of systemic venous blood,wherein conductivity of the systemic venous blood is measured as theconductivity difference between systemic venous blood at the dialyzerinlet and dialysis liquid at the dialyzer inlet.
 39. The apparatus ofclaim 38, further comprising means for measuring the conductivity of thesystemic venous blood, including: means for stopping a blood flow in theblood circuit for a time period sufficient to allow the cardiopulmonarycirculation to equalize; means for starting the blood flow in theexternal blood circuit with a slow speed to fill the blood removal linewith fresh blood before the measurement; means for measuring anequalized conductivity of the dialysate at a low dialysate flow rate orat isolated ultrafiltration.